Vestibular prosthesis: from basic research to clinics.

Balance disorders are highly prevalent worldwide, causing substantial disability with high personal and socioeconomic impact. The prognosis in many of these patients is poor, and rehabilitation programs provide little help in many cases. This medical problem can be addressed using microelectronics by combining the highly successful cochlear implant experience to produce a vestibular prosthesis, using the technical advances in micro gyroscopes and micro accelerometers, which are the electronic equivalents of the semicircular canals (SCC) and the otolithic organs. Reaching this technological milestone fostered the possibility of using these electronic devices to substitute the vestibular function, mainly for visual stability and posture, in case of damage to the vestibular endorgans. The development of implantable and non-implantable devices showed diverse outcomes when considering the integrity of the vestibular pathways, the device parameters (current intensity, impedance, and waveform), and the targeted physiological function (balance and gaze). In this review, we will examine the development and testing of various prototypes of the vestibular implant (VI). The insight raised by examining the state-of-the-art vestibular prosthesis will facilitate the development of new device-development strategies and discuss the feasibility of complex combinations of implantable devices for disorders that directly affect balance and motor performance.

Galvanic vestibular stimulation activates the parietal and temporal cortex in humans: A functional near-infrared spectroscopy (fNIRS) study.

Galvanic vestibular stimulation (GVS) helps stabilize subjects when balance and posture are compromised. This work aimed to define the cortical regions that GVS activates in normal subjects. We used functional near-infrared spectroscopy (fNIRS) to test the hypothesis that GVS activates similar cortical areas as a passive movement. We used transcranial current stimulation (cathode in the right mastoid process and anode in the FPz frontopolar point) of bipolar direct current (2 mA), false GVS (sham), vibration (neutral stimulus), and back and forth motion (positive control of vestibular movement) in 18 clinically healthy volunteers. Seventy-two brain scans were performed, applying a crossover-type experimental design. We measured the heart rate, blood pressure, body temperature, head capacitance, and resistance before and after the experiment. The haemodynamic changes of the cerebral cortex were recorded with an arrangement of 26 channels in four regions to perform an ROI-level analysis. The back-and-forth motion produced the most significant oxygenated haemoglobin (HbO2 ) increase. The response was similar for the GVS stimulus on the anterior and posterior parietal and right temporal regions. Sham and vibrational conditions did not produce significant changes ROI-wise. The results indicate that GVS produces a cortical activation coherent with displacement percept.

Resultados a siete años de la cirugía de reemplazo valvular aórtico en mayores de 80 años / Seven-year results of aortic valve replacement surgery in patients over 80 years of age

Resumen Objetivo: Describir las características clínicas y los resultados operatorios y a siete años del reemplazo valvular aórtico en una cohorte de pacientes mayores de 80 años. Materiales y métodos: Estudio descriptivo retrospectivo de 75 pacientes consecutivos mayores de 80 años, intervenidos de reemplazo valvular aórtico exclusivo entre 2007 y 2019 en el Hospital Guillermo Grant Benavente. Se estudian sus características demográficas, clínicas, ecocardiográficas, riesgo operatorio, cirugías, complicaciones y mortalidad operatoria y supervivencia alejada hasta el 15 de marzo 2021. Resultados: La edad media de la cohorte fue 83,05 ± 2,9 años (rango 80-95) y 43 pacientes eran mujeres (57,3%). La lesión valvular predominante fue la estenosis aórtica (89,3%). 10 pacientes tenían enfermedad coronaria asociada (13,3%) y 2 endocarditis activa. El riesgo de mortalidad operatoria calculado por EuroSCORE aditivo, logístico, II y STS score fue 7,58 ± 1,8; 9,88 ± 6,5%; 3,72 ± 3,5% y 4,27 ± 3,2%, respectivamente. Se utilizó prótesis biológica en 70 (92%) pacientes. Hubo 29 complicaciones operatorias y fallecieron 11 (14,7%) pacientes. El seguimiento promedio fue 7,1 años (rango 2-14), durante el cual fallecen 28 pacientes. La supervivencia a uno, tres y cinco años fue 82, 76, 66 y 48% respectivamente. Conclusiones: La cirugía de reemplazo valvular aórtico en octogenarios en nuestro medio es un procedimiento poco frecuente. La mortalidad observada fue mayor que la estimada por las escalas de riesgo. El reemplazo valvular quirúrgico es una alternativa de tratamiento de la enfermedad de la válvula aórtica en pacientes seleccionados. Se deben evaluar estrategias para mejorar los resultados.

Abstract Objective: To describe the clinical characteristics and operative and 7-year results of aortic valve replacement in a cohort of patients older than 80 years. Materials and methods: Retrospective descriptive study of 75 consecutive patients older than 80 years of age who underwent exclusive aortic valve replacement between 2007 and 2019 at the Guillermo Grant Benavente Hospital. Demographic, clinical, echocardiographic characteristics, operative risk, surgeries, complications and operative mortality and long-term survival until March 15, 2021 are studied. Results: The mean age of the cohort was 83.05 ± 2.9 years (range 80-95) and 43 patients were women (57.3%). The predominant valve lesion was aortic stenosis (89.3%). Ten patients had an associated coronary artery disease (13.3%) and 2 had active endocarditis. The risk of operative mortality calculated by EuroSCORE additive, logistic, II and STS score was 7.58 ± 1.8; 9.88 ± 6.5%; 3.72 ± 3.5% and 4.27 ± 3.2%, respectively. A biological prosthesis was used in 70 (92%) patients. There were 31 operative complications and 11 (14.7%) patients died. The mean follow-up was 7.1 years (range 2-14), during which 28 patients died. Survival at 1, 3, and 5 years was 82, 76, 66 and 48%, respectively. Conclusions: Aortic valve replacement surgery in octogenarians in our setting is a rare procedure. The observed mortality was higher than that estimated by the risk scales. Surgical valve replacement is an alternative treatment for aortic valve disease in selected patients. Strategies to improve results should be evaluated.

Opioid receptor activation modulates the calcium current in the cochlear outer hair cells of the rat.

Previous works showed that opioid peptides are produced by olivocochlear efferent neurons, while cochlear hair cells express opioid receptors. It has been proposed that opioids protect the auditory system from damage by intense stimulation, although their use for therapeutic or illicit purposes links to hearing impairment. Therefore, it is relevant to study the effect of opioids in the auditory system to define their functional expression and mechanism of action. This study investigated the modulation of the Ca2+ currents by opioid peptides in the rat outer hair cells (OHC) using the whole-cell patch-clamp technique. The influence of agonists of the three opioid receptor subtypes (µ, δ, and κ) was studied. The κ opioid receptor agonist U-50488 inhibits the Ca2+ currents in a partially reversible form. Coincidently, norbinaltorphimine (a κ receptor antagonist) blocked the U-50488 inhibitory effect on the Ca2+ current. The δ and the µ opioid receptor agonists did not significantly affect the Ca2+ currents. These results indicate that the κ opioid receptor activation inhibits the Ca2+ current in OHC, modulating the intracellular Ca2+ concentration when OHCs depolarize. The modulation of the auditory function by opioids constitutes a relevant mechanism with a potential role in the physiopathology of auditory disturbances.

A transient decrease in heart rate with unilateral and bilateral galvanic vestibular stimulation in healthy humans.

The study of cardiovascular function with galvanic vestibular stimulation has provided evidence on the neural structures that are involved in the vestibulo-autonomic reflex. This study determined if the effect on heart rate using galvanic vestibular stimulation persists after provoking a sympathetic response and if this response differs when using unilateral or transmastoid (bilateral) stimulation. We analysed heart rate and heart rate variability using unilateral and transmastoid galvanic vestibular stimulation combined with cardiovascular reflex evoked by postural change in 24 healthy human subjects. Three electrode configurations were selected for unilateral stimulation considering the anatomical location of each semicircular canal. We compared recordings performed in seated and standing positions, and with unilateral and transmastoid stimulation. With subjects seated, a significant transient decrease in heart rate was observed with unilateral stimulation. With transmastoid stimulation, heart rate decreased in both seated and standing positions. Average intervals between normal heartbeats recorded with stimulation resemble parasympathetic cardiac function induced by auricular vagal nerve stimulation. Our results indicate that unilateral stimulation does not eliminate the natural heart rate increase caused by orthostatic hypotension. In contrast, transmastoid stimulation provoked a transient reduction in heart rate, even when subjects were standing. These responses should be considered while performing experiments with galvanic vestibular stimulation and subsequent effects in cardiac regulation mechanisms.

Variablilidad de la presión arterial, hipertensión arterial nocturna y su asociación con tabaquismo / Blood pressure variability, nocturnal hypertension and its association with smoking / Variabilidade da pressão arterial, hipertensão arterial noturna e sua associação com o tabagismo

Resumen: Introducción: La hipertensión arterial y el tabaquismo son factores de riesgo independientes para el desarrollo de eventos cardiovasculares. El consumo de tabaco determina una elevación aguda de la presión arterial por acción del sistema simpático. Sin embargo los efectos a largo plazo son contradictorios. El aumento de la variabilidad de la presión arterial y la presencia de hipertensión arterial nocturna se asocia con eventos cardiovasculares adversos independientemente de los niveles de presión arterial. Objetivos: Evaluar la asociación entre tabaquismo e hipertensión arterial diurna, nocturna y variabilidad. Material y Métodos: Estudio analítico, observacional, transversal, multicéntrico, que incluye pacientes hipertensos mayores de 18 años con monitoreo ambulatorio de la presión arterial (MAPA). Resultados: Se incluyeron 391 pacientes, siendo 14.6% fumadores. Se encontraron cifras de presión arterial diurna sistólica y diastólica más elevadas en pacientes tabaquistas (p=0.204, p=0.087, respectivamente). Se observó una asociación significativa entre la hipertensión arterial nocturna y la presencia de diabetes mellitus e índice de masa corporal aumentado. No se encontró asociación entre el consumo de tabaco y los distintos patrones de variabilidad, así como tampoco con la hipertensión arterial nocturna. Conclusiones: El grupo de pacientes fumadores presentó una tendencia a cifras de presión arterial media diurna sistólica y diastólica más elevadas que los no fumadores, lo que podría sugerir que el tabaquismo incide en el control de cifras de presión arterial.

Abstract: Introduction: Hypertension and smoking are independent risk factors for the development of cardiovascular events. Tobacco use causes an acute elevation of blood pressure due to the action of the sympathetic system. However, the long-term effects are contradictory. Increased variability in blood pressure and the presence of nocturnal arterial hypertension are associated with adverse cardiovascular events regardless of blood pressure levels. Objectives: To evaluate the association between smoking and daytime and nighttime arterial hypertension and variability. Material and Methods: Analytical, observational, cross-sectional, multicenter study, which includes hypertensive patients over 18 years of age with ambulatory blood pressure monitoring (ABPM). Results: 391 patients were included, being 14.6% smokers. Higher levels of systolic and diastolic daytime blood pressure were found in smoking patients (p = 0.204, p = 0.087, respectively). A significant association was observed between nocturnal arterial hypertension and the presence of diabetes mellitus and increased body mass index. No association was found between tobacco consumption and the different patterns of variability, as well as with nocturnal arterial hypertension. Conclusions: The group of smoking patients showed a trend towards higher mean daytime systolic and diastolic blood pressure figures than non-smokers, which could suggest that smoking affects the control of blood pressure numbers.

Resumo: Introdução: Hipertensão e tabagismo são fatores de risco independentes para o desenvolvimento de eventos cardiovasculares. O uso do tabaco provoca elevação aguda da pressão arterial devido à ação do sistema simpático. No entanto, os efeitos de longo prazo são contraditórios. O aumento da variabilidade da pressão arterial e a presença de hipertensão arterial noturna estão associados a eventos cardiovasculares adversos, independentemente dos níveis de pressão arterial. Objetivos: Avaliar a associação entre tabagismo e hipertensão arterial diurna e noturna e variabilidade. Materiai e Métodos: Estudo analítico, observacional, transversal, multicêntrico, que inclui hipertensos maiores de 18 anos com monitorização ambulatorial da pressão arterial (MAPA). Resultados: Foram incluídos 391 pacientes, sendo 14,6% tabagistas. Níveis mais elevados de pressão arterial diurna sistólica e diastólica foram encontrados em pacientes fumantes (p = 0,204, p = 0,087, respectivamente). Foi observada associação significativa entre hipertensão arterial noturna e presença de diabetes mellitus e aumento do índice de massa corporal. Não foi encontrada associação entre o consumo de tabaco e os diferentes padrões de variabilidade, bem como com a hipertensão arterial noturna. Conclusões: O grupo de pacientes fumantes apresentou tendência a valores médios de pressão arterial sistólica e diastólica mais elevados do que os não fumantes, o que pode sugerir que o tabagismo afeta o controle dos valores da pressão arterial.

Nociceptin/orphanin FQ peptide receptor mediates inhibition of N-type calcium currents in vestibular afferent neurons of the rat.

The vestibular system is modulated by various neuromodulators including opioid peptides. The current study was conducted to determine whether activation of nociceptin/orphanin FQ peptide (NOP) receptors modulates voltage-gated calcium currents and action potential discharge of rat vestibular afferent neurons. We performed whole cell patch-clamp recordings on cultured vestibular afferent neurons from P7-P10 Long-Evans rats. Application of nociceptin/orphanin FQ (N/OFQ), a 17-amino acid neuropeptide that is the endogenous ligand for NOP receptor, inhibits the high-voltage activated (HVA) component of the calcium current in a concentration-dependent manner with a half inhibitory concentration of 26 nM. Said inhibitory action on the calcium current is voltage-dependent, which was made clear by the fact that it was reverted in 80% by a depolarizing prepulse. Furthermore, the effect of N/OFQ was blocked by application of the specific NOP-antagonist UFP101, by preincubation with G-protein blocker pertussis toxin, and by coapplication of the specific N-type calcium-current blocker ω-conotoxin-MVIIA. N/OFQ application causes an increase in the duration and maximum rate of repolarization of action potentials. It also decreases repetitive discharge and discharge elicited by sinusoidal stimulation. These results show that in vestibular afferents, NOP receptor activation inhibits N-type calcium current by activating G proteins, mostly through the Gßγ subunit. This suggests that NOP activation produces a presynaptic modulation of primary vestibular afferent neurons' output into the vestibular nuclei, thus taking part in the integration and gain setting of vestibular information in second-order vestibular nucleus neurons.NEW & NOTEWORTHY Our results show that in primary vestibular afferent neurons, activation of the nociceptin/orphanin FQ peptide receptor inhibits the N-type calcium current by a mechanism mediated by G proteins. We propose that calcium current inhibition modulates neurotransmitter release from vestibular afferents, producing a presynaptic modulation of vestibular input to vestibular nuclei, thus contributing to gain control in the vestibular afferent input.

Cigarrillo electrónico y otros sistemas electrónicos de liberación de nicotina: revisión de evidencias sobre un tema controversial / Electronic cigarette and other electronic nicotine delivery systems: a review of evidence on a controversial topic / Cigarro eletrônico e outros sistemas eletrônicos de liberação de nicotina: revisão de evidências sobre um tema controverso

Resumen: Introducción: los cigarrillos electrónicos (CE) son sistemas que liberan aerosol conteniendo nicotina y otras sustancias. Desde su aparición han generado una gran controversia en la comunidad científica dedicada al control de tabaco, existiendo evidencias que los posicionan como una alternativa de tratamiento para la cesación tabáquica y otros estudios que muestran sus daños a la salud, así como convertirlos en la puerta de entrada a los jóvenes a la adicción a nicotina. Objetivo: recopilar evidencia disponible sobre CE con referencia a componentes, riesgos para la salud, cesación de tabaquismo, impacto poblacional y aspectos normativos y regulatorios. Método: revisión narrativa. Se realizó búsqueda bibliográfica en bases PubMed, MEDLINE, SCOPUS, Redalyc, SciELO, LiLACS, Dialnet, ScienceDirect, así como en documentos de la Organización Mundial de la Salud, sociedades científicas, sitios web dedicados a consumidores y legislación nacional e internacional. Resultados: se revisaron 130 documentos, de los cuales se toman los 63 más relevantes. Existen evidencias científicas sobre contenidos tóxicos y carcinógenos en líquidos y aerosoles de los CE, así como de daño a la salud cardiovascular y respiratoria. Se presentan estudios controversiales sobre su eficacia para dejar de fumar. Se presenta evidencia acerca de cómo los CE impactan negativamente en la iniciación de jóvenes al consumo y en la recaída de exfumadores. Se analiza la normativa nacional e internacional para regular los CE. Conclusiones: los profesionales de la salud no deben aconsejar el uso de CE, dado que no son seguros y exponen a los consumidores y a la población en general de los efectos deletéreos directos e indirectos de los CE.

Summary: Introduction: e-cigarettes are systems that produce and release aerosol that contains nicotine and other substances. They have been controversial in the scientific community that works on tobacco control ever since they were created. There is evidence suggesting they are an alternative therapy for tobacco cessation and other studies prove they are harmful to health, and they end up being the door that welcomes young people to the world of nicotine addiction. Objective: to collect evidence on e-cigarette in connection with: components, risks to the health, tobacco cessation, impact on the population and normative and regulatory aspects. Method: Review of the literature. Bibliographic search on PubMed, MEDLINE, SCOPUS, Redalyc, Scielo, LiLACS, Dialnet, ScienceDirect, as well as in other documents of the World Health Organization, scientific societies, websites dedicated to consumers and the national and international laws. Results: 130 documents were reviewed, and the 63 most relevant ones served as the grounds for the study. There is scientific evidence on the toxic and carcinogenic content of liquids and aerosols of e-cigarettes, as well as on their negative effect on cardiovascular and respiratory health. We present controversial studies on its effectiveness to give up smoking, evidence on how e-cigarettes have a negative influence on the initiation of consumption by the young and on ex-smokers relapse. The study also analyses the national and international norms regulating e-cigarettes. Conclusions: health professionals must not recommend the use of e-cigarettes, since they are not safe and expose consumers and the general population to its direct and indirect harmful effects.

Resumo: Introdução: os cigarros eletrônicos (CE) são sistemas que liberam aerossol contendo nicotina e outras substâncias. Desde seu surgimento geraram uma grande controvérsia na comunidade científica dedicada ao controle do tabaco, existindo evidências que os colocam como uma alternativa de tratamento para a cessação do tabagismo e outros estudos que mostram seus danos à saúde, e como se transformam na porta de entrada dos jovens a adição a nicotina. Objetivo: recuperar a evidência disponível sobre CE com referência a: componentes, riscos para a saúde, cessação de tabagismo, impacto populacional e aspectos normativos e regulamentares. Método: revisão narrativa. Fez-se uma pesquisa bibliográfica nas bases PubMed, MEDLINE, SCOPUS, Redalyc, Scielo, LiLACS, Dialnet, ScienceDirect, e também em publicações da Organização Mundial da Saúde, sociedades científicas, sites web dedicados a consumidores e legislação nacional e internacional. Resultados: foram selecionados os 63 documentos mais relevantes dos 130 recuperados. Existem evidências científicas sobre conteúdos tóxicos e carcinogênicos em líquidos e aerossóis dos CE e também dos danos à saúde cardiovascular e respiratória. Apresentam-se estudos controversos sobre sua eficácia para apoiar o abandono do hábito de fumar e evidência de como os CE têm um impacto negativo na iniciação de jovens ao consumo e na recaída de ex- fumantes. Faz-se uma análise das normas nacionais e internacionais para regular os CE. Conclusões: os profissionais de saúde não devem aconselhar o uso de CE por não ser seguros e por que expõem os consumidores e a população em geral aos efeitos deletérios diretos e indiretos de seu uso.

Opioid modulation of cochlear auditory responses in the rat inner ear.

The auditory system has an extensive efferent innervation, which contributes to processes of control and regulation of the afferent input. The expression of receptors to various neurotransmitters and neuropeptides in the inner ear has been described, among which endogenous opioid receptors are found. The role of opioid receptors in the cochlea is not yet fully defined, it has been reported that opioid agonists and antagonists modulate the response to auditory stimuli and in clinical practice, multiple cases have been reported in which the consumption of opioid derivatives induce sensorineural hearing loss. In this work, we evaluated the effects of acute treatment with morphine, fentanyl, tramadol, and naloxone, in the auditory brain stem potentials (ABR), the compound action potential (CAP), and distortion products otacoustic emissions (DPOAE), across a wide range of stimulus frequencies and amplitudes. Adult Long-Evans rats of the strain CII/ZV weighing 180-220 g were used. For the ABR recording drugs were administered intraperitoneally or intravenously. For the CAP and DPOAE drugs were applied by direct perfusion in the middle ear. The opioid agonists produced a consistent increase in the amplitude of the PI component of the ABR and of the N1-P1 amplitude of the CAP. Naloxone produced no significant changes in the ABR and a reduction of the CAP N1-P1 amplitude. Also, opioid agonists induced a decrease in the amplitude of the DPOAE. These results show that the opioid receptor activation modulates both the afferent response at both the afferent response to acoustic stimuli, and also at the cochlear mechanics as revealed by DPOAE changes. These results present a significant step in understanding how opioid modulation of auditory responses may contribute to the auditory processing and to sensorineural hearing loss produced by opioids.

Sa12b Peptide from Solitary Wasp Inhibits ASIC Currents in Rat Dorsal Root Ganglion Neurons.

In this work, we evaluate the effect of two peptides Sa12b (EDVDHVFLRF) and Sh5b (DVDHVFLRF-NH2) on Acid-Sensing Ion Channels (ASIC). These peptides were purified from the venom of solitary wasps Sphex argentatus argentatus and Isodontia harmandi, respectively. Voltage clamp recordings of ASIC currents were performed in whole cell configuration in primary culture of dorsal root ganglion (DRG) neurons from (P7-P10) CII Long-Evans rats. The peptides were applied by preincubation for 25 s (20 s in pH 7.4 solution and 5 s in pH 6.1 solution) or by co-application (5 s in pH 6.1 solution). Sa12b inhibits ASIC current with an IC50 of 81 nM, in a concentration-dependent manner when preincubation application was used. While Sh5b did not show consistent results having both excitatory and inhibitory effects on the maximum ASIC currents, its complex effect suggests that it presents a selective action on some ASIC subunits. Despite the similarity in their sequences, the action of these peptides differs significantly. Sa12b is the first discovered wasp peptide with a significant ASIC inhibitory effect.

Sa12b peptide from solitary wasp inhibits ASIC currents in rat dorsal root ganglion neurons

In this work, we evaluate the effect of two peptides Sa12b (EDVDHVFLRF) and Sh5b (DVDHVFLRF-NH2) on Acid-Sensing Ion Channels (ASIC). These peptides were purified from the venom of solitary wasps Sphex argentatus argentatus and Isodontia harmandi, respectively. Voltage clamp recordings of ASIC currents were performed in whole cell configuration in primary culture of dorsal root ganglion (DRG) neurons from (P7-P10) CII Long-Evans rats. The peptides were applied by preincubation for 25 s (20 s in pH 7.4 solution and 5 s in pH 6.1 solution) or by co-application (5 s in pH 6.1 solution). Sa12b inhibits ASIC current with an IC50 of 81 nM, in a concentration-dependent manner when preincubation application was used. While Sh5b did not show consistent results having both excitatory and inhibitory effects on the maximum ASIC currents, its complex effect suggests that it presents a selective action on some ASIC subunits. Despite the similarity in their sequences, the action of these peptides differs significantly. Sa12b is the first discovered wasp peptide with a significant ASIC inhibitory effect.

Sa12b peptide from solitary wasp inhibits ASIC currents in rat dorsal root ganglion neurons

In this work, we evaluate the effect of two peptides Sa12b (EDVDHVFLRF) and Sh5b (DVDHVFLRF-NH2) on Acid-Sensing Ion Channels (ASIC). These peptides were purified from the venom of solitary wasps Sphex argentatus argentatus and Isodontia harmandi, respectively. Voltage clamp recordings of ASIC currents were performed in whole cell configuration in primary culture of dorsal root ganglion (DRG) neurons from (P7-P10) CII Long-Evans rats. The peptides were applied by preincubation for 25 s (20 s in pH 7.4 solution and 5 s in pH 6.1 solution) or by co-application (5 s in pH 6.1 solution). Sa12b inhibits ASIC current with an IC50 of 81 nM, in a concentration-dependent manner when preincubation application was used. While Sh5b did not show consistent results having both excitatory and inhibitory effects on the maximum ASIC currents, its complex effect suggests that it presents a selective action on some ASIC subunits. Despite the similarity in their sequences, the action of these peptides differs significantly. Sa12b is the first discovered wasp peptide with a significant ASIC inhibitory effect.

Cesación tabáquica en la salud cardiovascular / Smoking cessation in cardiovascular health

Resumen: La Organización Mundial de la Salud ha determinado que las enfermedades no transmisibles (ENT) constituyen uno de los mayores desafíos del presente siglo, ya que representan el 71% de las muertes que se registran en el mundo. El tabaquismo se considera uno de los principales factores de riesgo modificables que afecta a las ENT. Existe amplia evidencia que relaciona el tabaco con las enfermedades cardiovasculares, en particular con la cardiopatía isquémica. Las Guías de Prevención Cardiovascular de la Sociedad Europea de Cardiología del año 2016 establecen como recomendación clase I, nivel de evidencia A, el dejar de fumar. El efecto de la nicotina genera una fuerte adicción que desencadena un síndrome de abstinencia al intentar el abandono del consumo de tabaco. Por lo tanto, resulta necesario estar familiarizado con las estrategias para el tratamiento de la adicción al tabaco, que comprenden: intervención mínima, recursos cognitivo-conductuales y tratamiento farmacológico como terapia de sustitución nicotínica, bupropión y vareniclina. Hasta el momento no se cuenta con la suficiente evidencia científica para recomendar los dispositivos electrónicos.

Summary: The World Health Organization has determined that Non- communicable Diseases are one of the greatest challenges of this century as they represent 71% of the deaths that occur in the world. Smoking is considered one of the main modifiable risk factors that affect Non-communicable Diseases. There is ample evidence linking tobacco with cardiovascular diseases, particularly with ischemic heart disease. The guidelines for Cardiovascular Prevention of the European Society of Cardiology of 2016, establish as recommendation class I, level of evidence A, the cessation of smoking. The effect of nicotine generates a strong addiction that triggers an abstinence syndrome when trying to quit smoking. Therefore, it is necessary to be familiar with the strategies for the treatment of tobacco addiction that include: minimal intervention, cognitive-behavioral resources and pharmacological treatment such as nicotinic substitution therapy, bupropion and varenicline. So far, there is not enough scientific evidence to recommend electronic devices.

Protons as Messengers of Intercellular Communication in the Nervous System.

In this review, evidence demonstrating that protons (H+) constitute a complex, regulated intercellular signaling mechanisms are presented. Given that pH is a strictly regulated variable in multicellular organisms, localized extracellular pH changes may constitute significant signals of cellular processes that occur in a cell or a group of cells. Several studies have demonstrated that the low pH of synaptic vesicles implies that neurotransmitter release is always accompanied by the co-release of H+ into the synaptic cleft, leading to transient extracellular pH shifts. Also, evidence has accumulated indicating that extracellular H+ concentration regulation is complex and implies a source of protons in a network of transporters, ion exchangers, and buffer capacity of the media that may finally establish the extracellular proton concentration. The activation of membrane transporters, increased production of CO2 and of metabolites, such as lactate, produce significant extracellular pH shifts in nano- and micro-domains in the central nervous system (CNS), constituting a reliable signal for intercellular communication. The acid sensing ion channels (ASIC) function as specific signal sensors of proton signaling mechanism, detecting subtle variations of extracellular H+ in a range varying from pH 5 to 8. The main question in relation to this signaling system is whether it is only synaptically restricted, or a volume modulator of neuron excitability. This signaling system may have evolved from a metabolic activity detection mechanism to a highly localized extracellular proton dependent communication mechanism. In this study, evidence showing the mechanisms of regulation of extracellular pH shifts and of the ASICs and its function in modulating the excitability in various systems is reviewed, including data and its role in synaptic neurotransmission, volume transmission and even segregated neurotransmission, leading to a reliable extracellular signaling mechanism.